Effects of TAK-480, a Novel Tachykinin NK2^|^ndash;Receptor Antagonist, on Visceral Hypersensitivity in Rabbits and Ricinoleic Acid^|^ndash;Induced Defecation in Guinea Pigs

Abstract

Abstract. TAK-480, 4-(difluoromethoxy)-N-((1R,2S)-2-(((3aR,4R,9bR)-4-(methoxymethyl)-2, 3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl)carbonyl)cyclohexyl)benzamide, is a novel tachykinin NK 2 -receptor antagonist. In this study, we investigated its antagonistic activity and efficacy in animal models of visceral hypersensitivity and stimulated bowel function which have been implicated to underlie the symptoms in irritable bowel syndrome (IBS). TAK-480 showed potent binding affinity for human NK 2 receptors with a marked species difference and a 10,000-fold selectivity versus NK 1 and NK 3 receptors. TAK-480 dose-dependently antagonized colonic contractions induced by administration of the NK 2 receptor-selective agonist beta-Ala 8 -NKA(4-10) (βA-NKA) in anesthetized rabbits. In a rabbit model of intracolonic zymosan-induced visceral hypersensitivity, TAK-480 markedly inhibited the visceromotor response to colorectal distension, in contrast to the moderate inhibition by the serotonin 5-HT 3 -receptor antagonist alosetron. In addition, TAK-480 suppressed ricinoleic acid-induced defecation without affecting spontaneous defecation in guinea pigs, whereas alosetron suppressed both. Furthermore, TAK-480 inhibited smooth muscle contractions produced by natural tachykinins (substance P, neurokinin A, and neurokinin B) as well as βA-NKA in an isolated human colon. In conclusion, the novel NK 2 -receptor antagonist TAK-480 improved visceral hypersensitivity and accelerated defecation without causing constipation in experimental animals. Furthermore, the potent functional blockade of NK 2 receptors in human colon might suggest the potential effectiveness of TAK-480 in IBS patients.

Novel therapeutic agents in neurogastroenterology: advances in the past year

“…Tachykinin NK-2 receptor is a major factor in tachykinin-induced smooth muscle contraction in human colon smooth muscle in vitro; the response consists of an excitatory component via direct action on the smooth muscle and an inhibitory component, possibly via nitrergic neurons (31). In a rabbit model of intracolonic zymosan-induced visceral hypersensitivity, the tachykinin NK-2 receptor antagonist, TAK-480, markedly inhibited the visceromotor response to colorectal distension (32), suggesting a reduction in visceral sensitivity.…”

Gender-Related Differences of Tachykinin NK2Receptor Expression and Activity in Human Colonic Smooth Muscle

“…Among the three tachykinin receptor subtypes, NK2 receptors have an important role in regulating human colonic motility. Numerous pharmacological studies using human colonic smooth muscle strips have revealed that the contractile effects of endogenous tachykinins are mediated by NK2 receptors (Croci et al, 1998;Cao et al, 2000;Liu et al, 2002;Liu et al, 2009;Nakamura et al, 2011;Tanaka et al, 2012). This is in line with the high mRNA expression levels of the TACR2 gene (encoding NK2 receptors) in human colonic smooth muscle (Liu et al, 2011).…”

Animal Models for Functional Gastrointestinal Disorders

“…Mustard oil, given orally, induces elongation of the transit time in the upper GI (esophagus) and a decreased transit time in the lower GI part (colon) (271). Ricinoleic acid-induced defecation in the guinea pig is suppressed by a specific tachykinin receptor NK2 antagonist (272).…”

“…In rabbits, intracolonic infusion of Zymosan leads to colonic hypersensitivity (272) which is reduced by a tachykinin NK2 receptor antagonist.…”